Blood Vessel Maturation and Response to Vascular-Disrupting Therapy in Single Vascular Endothelial Growth Factor-A Isoform–Producing Tumors

Tozer, Gillian M, Akerman, Simon, Cross, Neil A, Barber, Paul R, Björndahl, Meit A, Greco, Olga, Harris, Sheila, Hill, Sally A, Honess, Davina J, Ireson, Christopher R, Pettyjohn, Katie L, Prise, Vivien E, Reyes-Aldasoro, Constantino C, Ruhrberg, Christiana, Shima, David T and Kanthou, Chryso (2008) Blood Vessel Maturation and Response to Vascular-Disrupting Therapy in Single Vascular Endothelial Growth Factor-A Isoform–Producing Tumors. Cancer Research, 68 (7). pp. 2301-2311. ISSN 0008-5472

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Abstract

Tubulin-binding vascular-disrupting agents (VDA) are currently in clinical trials for cancer therapy but the factors that influence tumor susceptibility to these agents are poorly understood. We evaluated the consequences of modifying tumor vascular morphology and function on vascular and therapeutic response to combretastatin-A4 3-O-phosphate (CA-4-P), which was chosen as a model VDA. Mouse fibrosarcoma cell lines that are capable of expressing all vascular endothelial growth factor (VEGF) isoforms (control) or only single isoforms of VEGF (VEGF120, VEGF164, or VEGF188) were developed under endogenous VEGF promoter control. Once tumors were established, VEGF isoform expression did not affect growth or blood flow rate. However, VEGF188 was uniquely associated with tumor vascular maturity, resistance to hemorrhage, and resistance to CA-4-P. Pericyte staining was much greater in VEGF188 and control tumors than in VEGF120 and VEGF164 tumors. Vascular volume was highest in VEGF120 and control tumors (CD31 staining) but total vascular length was highest in VEGF188 tumors, reflecting very narrow vessels forming complex vascular networks. I.v. administered 40 kDa FITC-dextran leaked slowly from the vasculature of VEGF188 tumors compared with VEGF120 tumors. Intravital microscopy measurements of vascular length and RBC velocity showed that CA-4-P produced significantly more vascular damage in VEGF120 and VEGF164 tumors than in VEGF188 and control tumors. Importantly, this translated into a similar differential in therapeutic response, as determined by tumor growth delay. Results imply differences in signaling pathways between VEGF isoforms and suggest that VEGF isoforms might be useful in vascular-disrupting cancer therapy to predict tumor susceptibility to VDAs.

Item Type: Article
Schools and Departments: School of Engineering and Informatics > Engineering and Design
Subjects: R Medicine > R Medicine (General) > R858 Computer applications to medicine. Medical informatics
R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology Including cancer and carcinogens
Depositing User: Constantino Reyes Aldasoro
Date Deposited: 24 Apr 2012 08:53
Last Modified: 08 Mar 2017 05:33
URI: http://sro.sussex.ac.uk/id/eprint/38697

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